Flipping the switch: dynamic modulation of membrane transporter activity in bacteria

Abstract

The controlled entry and expulsion of small molecules across the bacterial cytoplasmic membrane is essential for efficient cell growth and cellular homeostasis. While much is known about the transcriptional regulation of genes encoding transporters, less is understood about how transporter activity is modulated once the protein is functional in the membrane, a potentially more rapid and dynamic level of control. In this review, we bring together literature from the bacterial transport community exemplifying the extensive and diverse mechanisms that have evolved to rapidly modulate transporter function, predominantly by switching activity off. This includes small molecule feedback, inhibition by interaction with small peptides, regulation through binding larger signal transduction proteins and, finally, the emerging area of controlled proteolysis. Many of these examples have been discovered in the context of metal transport, which has to finely balance active accumulation of elements that are essential for growth but can also quickly become toxic if intracellular homeostasis is not tightly controlled. Consistent with this, these transporters appear to be regulated at multiple levels. Finally, we find common regulatory themes, most often through the fusion of additional regulatory domains to transporters, which suggest the potential for even more widespread regulation of transporter activity in biology.

A flow equilibrium of zinc in cells of Cupriavidus metallidurans

“…Regulation of the zinc uptake and efflux activities could have been done by flux control, for example, by binding of metal ions to the regulatory sites of the transporter ( 35 , 36 , 45 , 46 ) or by interaction with other proteins, degradation of uptake or de novo synthesis of efflux systems. Expression of a gene for a copper-exporting P-type ATPase at 37°C in Escherichia coli needed just 2 min to reach an abundance peak for the transcript ( 47 ) and 10 min for a czc transcript at 30°C in C. metallidurans ( 48 ).…”

“…The uptake and efflux systems of C. metallidurans strain AE104 may be responsible for the cellular zinc content as the result of a kinetical flow equilibrium with the activity of the individual transport systems regulated by gene expression, flux control, and other processes ( 5 , 35 , 36 ). Such a flow equilibrium would be a futile cycle that is required to constantly adjust the composition of the cellular metal pool and the concentration of each metal, all in cooperation with the metal-binding capacity of the cytoplasm.…”